DK150602B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS Download PDFInfo
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Description
150602150602
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af alkylaminpropanolderivater af 3-alkyl-5-(2-hydroxy.-styryl)-isoxazol eller fysiologisk acceptable syreadditionssalte heraf af den i 5 indledningen til kravet angivne art, hvilke forbind elser kan anvendes som værdifulde lægemidler ved behandling af hypertoni, coronare hjertesygdomme og hjerterytmeforstyrrelser. Forbindelserne er hidtil ukendte.The present invention relates to an analogous process for the preparation of alkylamine propanol derivatives of 3-alkyl-5- (2-hydroxy-styryl) -isoxazole or physiologically acceptable acid addition salts thereof of the kind set forth in the preamble to the claim, which compounds can be used as valuable drugs. in the treatment of hypertension, coronary heart disease and heart rhythm disorders. The compounds are novel.
10 Det har vist sig, at forbindelser med den almene formel IIt has been found that compounds of the general formula I
R' i o'^V^'nhrR 'i o' ^ V ^ 'nhr
OHOH
hvori R betegner en alkylgruppe med 1-8 C-atomer, en alkenyl- eller alkynylgruppe med 2-8 C-atomer, en cycloalkylgruppe med 3-8 C-atomer i ringen, og R1 be-15 tegner en alkylgruppe med 1-4 C-atomer, eller fysiologisk acceptable syreadditionssalte heraf udviser værdifulde farmakologiske egenskaber.wherein R represents an alkyl group of 1-8 C atoms, an alkenyl or alkynyl group of 2-8 C atoms, a cycloalkyl group of 3-8 C atoms in the ring, and R 1 represents an alkyl group of 1-4 C atoms, or physiologically acceptable acid addition salts thereof, exhibit valuable pharmacological properties.
Forbindelserne kan karakteriseres som farmakodynamisk højaktive β-sympatholytika med akut blodtryksænkende 20 eller antihypertensiv virkning. Denne virkningstype er i og for sig usædvanlig, da kendte i3-sympatholytika, f.eks. propranolol, kun virker antihypertensive ved længere varende indgift.The compounds can be characterized as pharmacodynamically highly active β-sympatholytics with acute blood pressure lowering or antihypertensive effect. This type of effect is unusual in itself, since known i3 sympatholytics, e.g. propranolol, only acts antihypertensive on longer-term administration.
På grund af de nævnte virkninger er de omhandlede for-25 bindeiser specielt farmakoterapeutisk egnede til behandling af hypertoni, coronare hjertesygdomme og af hjerterytmeforstyrrelser.Due to the aforementioned effects, the present compounds are particularly pharmacotherapeutically useful in the treatment of hypertension, coronary heart disease and heart rhythm disorders.
150602 2150602 2
Blandt alkylgrupperne foretrækkes sådanne, der indeholder en forgrening ved det α-stående carbonatom til aminnitrogenet. Foretrukne alkylgrupper er isopropyl og tert.-butyl.Among the alkyl groups, those containing a branching at the α-standing carbon atom to the amine nitrogen are preferred. Preferred alkyl groups are isopropyl and tert-butyl.
5 Cycloalkylgrupper er for eksempel cyclopropyl, cyclo- butyl, cyclopentyl og cyclohexyl. Cyclopropylgruppen foretrækkes.Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclopropyl group is preferred.
Som alkylgrupper for R' med 1-4 C-atomer, der er lige eller forgrenede, kan nævnes methyl, ethyl, propyl, 10 isopropyl, n-butyl, sek.-butyl og tert.-butyl. Heraf foretrækkes methyl og ethyl.As alkyl groups for R 'having 1-4 C atoms that are straight or branched can be mentioned methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Of this, methyl and ethyl are preferred.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man omsætter en 3-alkyl-5-styryl-isoxazol med den almene formel IIThe process of the invention is characterized by reacting a 3-alkyl-5-styryl-isoxazole of the general formula II
_ R*_ R *
^O-CH2-A^ O-CH2-A
15 hvori A betegner gruppenWherein A represents the group
O OHO OH
/ \ og/eller I/ \ and / or I
-CH - CH2 -CH-CH2-B, idet B betegner en nukleofug fraspaltningsgruppe, og R' har den i formel I angivne betydning, med en amin med den almene formel 20 H2N-R, 3 150802 hvori R har den i formel I angivne betydning, hensigtsmæssigt i et opløsningsmiddel og eventuelt i nærværelse af et syrebindende middel, ved temperaturer på fra 10 til 120 °C, og at man eventuelt overfører den således opnåede for-5 bindelse til et syreadditionssalt med en fysiologisk acceptabel syre.-CH - CH2 -CH-CH2-B, wherein B represents a nucleophile cleavage group and R 'is as defined in formula I, with an amine of the general formula H 2 N-R, R 3 wherein R is as in formula I of meaning, conveniently in a solvent and optionally in the presence of an acid binding agent, at temperatures of from 10 to 120 ° C and optionally transferring the thus obtained compound to an acid addition salt with a physiologically acceptable acid.
Fraspaltningsgruppen B betegner fortrinsvis et halogenatom, specielt chlor, brom eller iod. Yderligere kommer eksempelvis aromatiske eller alifatiske sulfonsyregrupper i be-10 tragtning som nukleofuge fraspaltningsgrupper, f.eks. p-toluensulfonsyre-, p-brombenzensulfonsyre- eller methan-sulfonsyregruppen.The leaving group B preferably represents a halogen atom, especially chlorine, bromine or iodine. Further, for example, aromatic or aliphatic sulfonic acid groups are considered as nucleofuge cleavage groups, e.g. the p-toluenesulfonic acid, p-bromobenzene sulfonic acid or methanesulfonic acid group.
Omsætningerne gennemføres ved temperaturer fra 10 til 120°C, dvs. ved stuetemperatur eller ved højere temperaturer, for-15 trinsvis ved temperaturer på 50 til 120°C. Omsætningen kan gennemføres under atmosfæretryk eller i en lukket beholder under forhøjet tryk, eventuelt under opvarmning til det angivne temperaturområde.The reactions are carried out at temperatures of 10 to 120 ° C, ie. at room temperature or at higher temperatures, preferably at temperatures of 50 to 120 ° C. The reaction may be carried out under atmospheric pressure or in a closed container under elevated pressure, optionally under heating to the specified temperature range.
Specielt ved let flygtige aminer H2N-R kan det være fordel-20 agtigt at gennemføre omsætningen i et lukket system, dvs. i en autoklav.Especially with slightly volatile amines H2N-R it may be advantageous to carry out the reaction in a closed system, ie. in an autoclave.
Udgangsforbindelserne kan omsættes direkte, dvs, uden tilsætning af et fortyndings- eller opløsningsmiddel. Hensigtsmæssigt udføres omsætningerne dog i nærværelse af et inert 25 fortyndings- eller opløsningsmiddel, f.eks. en lavere alkohol med 1-4 C-atomer, såsom methanol, ethanol eller propanol, fortrinsvis isopropanol eller ethanol, en lavere mættet dialkylether, dialkylglycolether eller cyclisk ether, som f.eks. diethylether, 1,2-dimethoxyethan, tetrahydrofuran 30 eller dioxan, en aromatisk carbonhydrid, som benzen selv, eller en alkylbenzen, specielt toluen eller xylen, eller en alifatisk carbonhydrid, som hexan, heptan eller octan, en lavere alifatisk keton, såsom acetone, methylethylketon eller methylisobutylketon, en dialkylformamid, som dimethyl- 150602 4 eller diethylformamid, i nærværelse af dimetylsulfoxid eller af vand eller i blandinger af ovennævnte opløsningsmidler.The starting compounds can be reacted directly, that is, without the addition of a diluent or solvent. Conveniently, however, the reactions are carried out in the presence of an inert diluent or solvent, e.g. a lower alcohol having 1-4 C atoms such as methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether such as e.g. diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene itself, or an alkylbenzene, especially toluene or xylene, or an aliphatic hydrocarbon such as hexane, heptane or octane, a lower aliphatic ketone such as acetone, methylethyl ketone or methyl isobutyl ketone, a dialkylformamide, such as dimethylformamide or diethylformamide, in the presence of dimethylsulfoxide or of water or in mixtures of the above solvents.
Den anvendte amin med formlen E^N-R er i overskud eventuelt egnet som opløsnings- eller fortyndingsmiddel.The amine of formula E EN-R used in excess is optionally suitable as a solvent or diluent.
5 Foretrukkent opløsningsmiddel ved omsætningen af 3-alkyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazoler med en amin R-NE^ er lavere alkoholer, specielt ethanol eller isopropanol, idet omsætningen fortrinsvis gennemføres ved temperaturer fra 50 til 120°C. Eventuelt kan omsætningen gennemføres 10 i en lukket beholder under tryk, specielt dersom lavere- kogende aminer anvendes. Ved den nucleofile substitution af en gruppe B foretrækkes som opløsningsmiddel en lavere alifatisk keton, som acetone, methylethylketon eller methyl-isobutylketon, en cyclisk alifatisk ether, specielt tetra-15 hydrofuran eller dioxan, eller en dialkylformamid, som dime thylformamid, og temperaturer fra 90 til 120°C. Eventuelt kan omsætningen gennemføres i nærværelse af en katalytisk mængde af natrium- eller kaliumiodid.Preferred solvent in the reaction of 3-alkyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazoles with an amine R-NE 2 are lower alcohols, especially ethanol or isopropanol, the reaction being preferably carried out at temperatures of 50 to 120 ° C. Optionally, the reaction may be carried out in a closed container under pressure, especially if lower boiling amines are used. In the nucleophilic substitution of a group B, a lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a cyclic aliphatic ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, such as dime thylformamide, and temperatures of 90 are preferred. to 120 ° C. Optionally, the reaction may be carried out in the presence of a catalytic amount of sodium or potassium iodide.
Det skal også nævnes, at en blanding af epoxid med et halo- 20 genhydrin også eventuelt kommer i betragtning som udgangsforbindelse med·formlen II, da der ved den tekniske fremstilling af udgangsforbindelserne under visse omstændigheder opstår blandinger.It should also be mentioned that a mixture of epoxide with a halogen hydrine is also optionally considered as a starting compound of formula II, since mixtures occur in the technical preparation of the starting compounds in certain circumstances.
Ved en hensigtsmæssig udførelsesform til nucleofil substi-25 tution af gruppen B med den anvendte amin gennemføres omsætningen i nærværelse af en base som syrebindende middel. Foretrukne baser er alkalimetalhydroxider, -carbonater, -hy-drogencarbonater, -alkoholater, specielt methylater og ethylater, eller en tertiær organisk amin, som pyridin eller en tri-30 alkylamin, som trimethylamin eller triethylamin. Af alkali-ruetalforbindelser kommer specielt forbindelser af natrium og 150602 5 kalium i betragtning. Til dette anvendes basen i en støkiometrisk mængde eller i et ringe overskud. Eventuelt er det hensigtsmæssigt samtidigt at anvende aminen der skal omsættes, i overskud som syrebindende middel.In an appropriate embodiment for nucleophilic substitution of group B with the amine used, the reaction is carried out in the presence of a base as an acid binding agent. Preferred bases are alkali metal hydroxides, carbonates, hydrogen carbonates, alcoholates, especially methylates and ethylates, or a tertiary organic amine, such as pyridine or a trialkylamine, such as trimethylamine or triethylamine. Particularly of alkali-crude metal compounds, sodium and potassium compounds are considered. For this, the base is used in a stoichiometric amount or in a slight excess. It may be appropriate to simultaneously use the amine to be converted in excess as an acid binding agent.
5 Den fuldstændige omsætning afhænger af reaktionstemperaturen og er sædvanligvis løbet til ende i løbet af 2 - 15 timer. Reaktionsproduktet kan udvindes på i og for sig sædvanlig måde, f.eks. ved filtrering eller afdestillation af opløsnings- eller fortyndingsmidlet fra reaktionsblandingen.The complete reaction depends on the reaction temperature and is usually completed within 2 - 15 hours. The reaction product can be recovered in a conventional manner, e.g. by filtration or distillation of the solvent or diluent from the reaction mixture.
10 Herefter renses på sædvanlig måde, f.eks. ved omkrystallisation ved hjælp af et opløsningsmiddel, overførsel til en syreadditionsforbindelse eller ved søjlekromatografi.10 is then purified in the usual manner, e.g. by recrystallization by a solvent, transfer to an acid addition compound or by column chromatography.
Udgangsforbindelserne med formel II kan fremstilles ved alkylering af en 3-alkyl-5-(2-hydroxy-styryl)-isoxazol, 15 som f.eks. er opnået i en Wittig-reaktion ud fra et di-alkyl-isoxazolyl-5-methylen-phosponat og et ved OH-grup-pen med en beskyttelsesgruppe udstyret salicylaldehyd ifølge DE offentliggørelsesskrift nr. 2 818 998, med en epihalogenhydrin eller en α,ω-dihalogen-2-propanol.The starting compounds of formula II may be prepared by alkylation of a 3-alkyl-5- (2-hydroxy-styryl) -isoxazole, such as e.g. is obtained in a Wittig reaction from a di-alkyl-isoxazolyl-5-methylene phosphate and a salicylaldehyde equipped with a protecting group with a protecting group according to DE Publication No. 2,818,998, with an epihalohydrin or an α, ω-dihalo-2-propanol.
20 Som epihalogenhydriner kommer epichlorhydrin, epibromhydrin og epiiodhydrin på tale, og som a,a/-dihalogen-2-propanol specielt l,3-dichlor-2-propanol og l,3-dibrom-2-propanol, i betragtning.As epihalohydrin, epichlorohydrin, epibromohydrin and epioiodohydrin are considered, and as α, α / -dihalogen-2-propanol especially 1,3-dichloro-2-propanol and 1,3-dibromo-2-propanol are considered.
Omsætningen af 3-alkyl-5-(2-hydroxy-styryl)-isoxazol til 25 fremstilling af udgangsforbindelserne med formel IX gennemføres hensigtsmæssigt ved temperaturer på fra 0 til 120°C og ved normaltryk eller i en lukket beholder under forhøjet tryk. Omsætningen udføres hensigtsmæssigt i et inert fortyndings- eller opløsningsmiddel, f.eks. en lavere alifatisk 30 keton, som acetone, methylethylketon eller methylisobutyl-keton, i en lavere alkohol med 1-4 C-atomer, som methanol, ethanol, propanol eller butanol, i en lavere alifatisk eller 6 150602 cyclisk ether, som diethylether, tetrahydrofuran eller dioxan, i en dialkyIformamid, som dimethylformamid eller diethyl-formamid, eller i dimethylsulfoxid og hexamethylphorphor-triamid eller med overskud af alkyleringsmidlet som fortyn-5 dings- eller opløsningsmiddel.The reaction of 3-alkyl-5- (2-hydroxy-styryl) -isoxazole to prepare the starting compounds of formula IX is conveniently carried out at temperatures of 0 to 120 ° C and at normal pressure or in a closed container under elevated pressure. The reaction is conveniently carried out in an inert diluent or solvent, e.g. a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, in a lower alcohol having 1-4 C atoms, such as methanol, ethanol, propanol or butanol, in a lower aliphatic or cyclic ether such as diethyl ether, tetrahydrofuran or dioxane, in a dialkylformamide, such as dimethylformamide or diethylformamide, or in dimethylsulfoxide and hexamethylphorphoramide, or with excess of the alkylating agent as a diluent or solvent.
Fortrinsvis foretages omsætningen i nærværelse af en base som syrebindende middel. Egnede baser er alkalimetalcar-bonater, -hydrogencarbonater, -hydroxider, -hydrider eller -alkoholater, specielt af natrium og kalium, basiske oxider, 10 som aluminiumoxid eller calciumoxid, organiske tertiære baser, som pyridin, piperidin eller en lavere trialkylamin, som trimethyl- eller triethylamin. Til dette formål kan baserne anvendes i et forhold til det anvendte alkyleringsmiddel i katalytisk mængde eller i støkiometrisk mængde 15 eller i et ringe overskud.Preferably, the reaction is carried out in the presence of a base as an acid binding agent. Suitable bases are alkali metal carbonates, hydrogen carbonates, hydroxides, hydrides or alcoholates, especially of sodium and potassium, basic oxides, such as alumina or calcium oxide, organic tertiary bases, such as pyridine, piperidine or a lower trialkylamine, such as trimethyl or triethylamine. For this purpose, the bases can be used in a ratio of the alkylating agent used in catalytic amount or in stoichiometric amount or in a small excess.
Fortrinsvis omsættes 3-alkyl-5-(2-hydroxy-styryl)-isoxazolen med epibromhydrin eller l,2-dibrompropanol-2 i et polært aprotisk opløsningsmiddel, specielt dimethylsulfoxid, i nærværelse af i det mindste et molækvivalent base, specielt 20 natriumhydrid, beregnet på alkyleringsmiddel, ved temperaturer på fra 0 til 50°C.Preferably, the 3-alkyl-5- (2-hydroxy-styryl) isoxazole is reacted with epibromohydrin or 1,2-dibromopropanol-2 in a polar aprotic solvent, especially dimethylsulfoxide, in the presence of at least one molar equivalent base, especially sodium hydride. calculated on alkylating agent, at temperatures of from 0 to 50 ° C.
Analogt med den i Liebigs Annalen der Chemie 1976, side 221 ' til 224 beskrevne fremgangsmåde til omsætning af phenol med l,3-dichlor-2-propanol kan også 3-alkyl-5-(2-hydroxy-styryl)-25 isoxazol omsættes med den ækvivalente mængde l,3-dichlor-2-propanol i vandig natronlud ved temperaturer omkring 50°C.Analogous to the process described for the reaction of phenol with 1,3-dichloro-2-propanol described in Liebigs Annalen der Chemie 1976, pages 221 'to 224, 3-alkyl-5- (2-hydroxy-styryl) -25 isoxazole can also be reacted. with the equivalent amount of 1,3-dichloro-2-propanol in aqueous baking soda at temperatures around 50 ° C.
Udgangsforbindelser med den almene formel II, hvori A betegner gruppen /°\ -CH - CH2 150602 7Starting compounds of the general formula II wherein A represents the group / ° / -CH - CH2
kan også fås ved, at man omsætter methanphosphonsyre-ester med den almene formel VIcan also be obtained by reacting methane phosphonic acid ester of the general formula VI
RHch2<0°2115 med det i J. Chem. Soc. London, 1974, 1571-1577 beskrevne o-(2,3-epoxypropoxy)-benzaldehyd. , 5 Til omsætning af o-(2,3-epoxypropoxy)-benzaldehyd med en phosphoran med formel VI kommer inerte organiske opløsningsmidler i betragtning som reaktionsmedium, som f.eks. en lavere mættet dialkylether, dialkylglycol-ether eller cycliske ethere, som diethylether, 1,2-10 dimethyloxyethan, tetrahydrofuran eller dioxan, benzen eller en alkylbenzen, som toluen eller xylen, en alifa-tisk carbonhydrid, som hexan, heptan eller oktan, di-methylsulfoxid, dimethylformamid eller blandinger af de nævnte opløsninger. Omsætningen gennemføres mellem 0° C 15 og det anvendte opløsningsmiddels kogetemperatur, fortrinsvis ved stuetemperatur, i løbet af 1 til 48 timer, fortrinsvis 1 til 16 timer, og fortrinsvis i en nitrogenatmosfære. Egnede baser til denne Wittig-Horner-reak-tion er alkalimetalhydrider, -amider eller -alkoholater, 20 specielt af natrium og kalium, fortrinsvis anvender man natriummethylat.RHch 2 <0 ° 2115 with that of J. Chem. Soc. London, 1974, 1571-1577 described o- (2,3-epoxypropoxy) -benzaldehyde. In reaction of o- (2,3-epoxypropoxy) -benzaldehyde with a phosphorane of formula VI, inert organic solvents are considered as reaction medium, e.g. a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ethers, such as diethyl ether, 1,2-10 dimethyloxyethane, tetrahydrofuran or dioxane, benzene or an alkylbenzene, such as toluene or xylene, an aliphatic hydrocarbon such as hexane, heptane or octane, di -methylsulfoxide, dimethylformamide or mixtures of said solutions. The reaction is carried out between 0 ° C and the boiling temperature of the solvent used, preferably at room temperature, over 1 to 48 hours, preferably 1 to 16 hours, and preferably in a nitrogen atmosphere. Suitable bases for this Wittig-Horner reaction are alkali metal hydrides, amides or alcoholates, especially of sodium and potassium, preferably sodium methylate is used.
De omhandlede forbindelser med formel I har ved den alifatiske sidekædes carbonatom 2 et kiralcentrum, og de kan fås som racemater, der ved velkendte metoder, f.eks.The present compounds of formula I have at the aliphatic side chain carbon atom 2 a chiral center and they can be obtained as racemates which by well known methods, e.g.
25 ved dannelse af diastereomere salte med optisk aktive hjælpesyrer, som dibenzoylsyre, campher-10-sulfonsyre, ditoluylvinsyre eller 3-brom-campher-8-sulfonsyre, kan adskilles i de optisk aktive antipoder.25 by forming diastereomeric salts with optically active auxiliary acids, such as dibenzoyl acid, campher-10-sulfonic acid, ditoluyl tartaric acid or 3-bromo-campher-8-sulfonic acid, can be separated into the optically active antipodes.
150602 88
Eventuelt overføres de opnåede omhandlede forbindelser i syreadditionssaltet med en fysiologisk acceptabel syre.Optionally, the obtained compounds are transferred into the acid addition salt with a physiologically acceptable acid.
Som sædvanlige fysiologisk acceptable organiske eller uorganiske syrer kommer for eksempel saltsyre, hydrogen-5 bromidsyre, phosphorsyre eller svovlsyre i betragtning og som organisk syrer, f.eks. oxalsyre, maleinsyre, fu-marsyre, mælkesyre, vinsyre, æblesyre, citronsyre, salicylsyre, adipinsyre eller benzoesyre i betragtning, eller de kan fås ud fra Fortschritte der Arzneimittelforschung, 10 bind 10, side 224 til 225, Birkhåuser forlag, Basel og Stuttgart, 1966, eller fra Journal of Pharmaceutical Sciences, Vol. 66, side 1 til 5 (1977).As usual physiologically acceptable organic or inorganic acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are considered and as organic acids, e.g. oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzoic acid, or they can be obtained from Fortschritte der Arzneimittelforschung, 10 vol. 10, pages 224 to 225, Birkhåuser publishers, Basel and Stuttgart, 1966, or from the Journal of Pharmaceutical Sciences, Vol. 66, pages 1 to 5 (1977).
Syreadditionssaltene fås som regel på i og for sig kendt måde ved blanding af den frie base eller opløsninger 15 heraf med den passende syre eller opløsninger heraf i et organisk opløsningsmiddel, f.eks. i en lavere alkohol som methanol, ethanol eller propanol, eller i en lavere keton, som acetone, methylethylketon eller methyliso-butylketon, eller i en ether, som diethylether, tetra-20 hydrofuran eller dioxan. For bedre at få udskillelse af krystaller kan blandinger af de nævnte opløsningsmidler anvendes. Herudover kan fremstilles farmaceutisk acceptable vandige opløsninger af syreadditionsforbindelserne af aminopropanol-derivatet med den almene for-25 mel I ved opløsning af den frie base med den almene formel I i en vandig syreopløsning.The acid addition salts are usually obtained in a manner known per se by mixing the free base or solutions thereof with the appropriate acid or solutions thereof in an organic solvent, e.g. in a lower alcohol such as methanol, ethanol or propanol, or in a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or in an ether such as diethyl ether, tetrahydrofuran or dioxane. For better separation of crystals, mixtures of the aforementioned solvents may be used. In addition, pharmaceutically acceptable aqueous solutions of the acid addition compounds of the aminopropanol derivative of the general formula I can be prepared by dissolving the free base of the general formula I in an aqueous acid solution.
Undersøgelsen for de farmakodynamiske egenskaber for de omhandlede forbindelser foretoges efter følgende metoder: 30 i. β-sympatholytisk virkning på isoproterenol-tachycardie hos narkotiserede katte.The study for the pharmacodynamic properties of the compounds of the invention was carried out according to the following methods: 30 in. Β-sympatholytic effect on isoproterenol-tachycardia in anesthetized cats.
Intravenøs tilførsel af 0,001 mg/kg af j^-sympathomime-tikaet isoproterenol forøger hjertefrekvensen hos ba 150602 9 stardkatte (vægt 2-4 kg) i hexobarbital-narkose (200 mg/kg intramuskulært) med gennemsnitligt 61 slag (40%).Intravenous administration of 0.001 mg / kg of the β-sympathomimetic isoproterenol increases the heart rate of ba standard cats (weight 2-4 kg) in hexobarbital anesthesia (200 mg / kg intramuscularly) with an average of 61 strokes (40%).
β-sympatholytika hæmmer denne frekvensstigning specifikt og dosisafhængende. Tilførselen af de forbindelser, der 5 skal undersøges, sker 10 minutter før isoproterenol til grupper på 3 - 5 katte pr. dosis.β-sympatholytics specifically inhibit this frequency increase and dose-dependence. The administration of the compounds to be tested occurs 10 minutes before isoproterenol to groups of 3 to 5 cats per day. dosage.
Som ED 50% anføres den dosis, som hæmmer isoproterenol- tachycardie med 50%.As ED 50%, indicate the dose which inhibits isoproterenol tachycardia by 50%.
2. Blodtryksænkende virkning på narkotiserede rotter.2. Blood pressure lowering effect on narcotic rats.
10 Til en undersøgelse af den blodtryksænkende virkning fik grupper på 3 - 5 han Sprague-Dawley-rotter (vægt: 230 - 280 g) i urethan-narkose (1,78 g/kg intraperi-tonealt) tilført forbindelserne intravenøst.10 For a study of the blood pressure lowering effect, groups of 3 to 5 male Sprague-Dawley rats (weight: 230-280 g) in urethane anesthesia (1.78 g / kg intraperitoneally) were administered intravenously.
Måling af blodtrykket i A.carotis sker over en Statham- 20 transducer.The blood pressure in A.carotis is measured over a Statham transducer.
Som ED 20% angives den dosis, som sænker middel-carotis- trykket med 20%.As ED 20%, indicate the dose which lowers mean carotid pressure by 20%.
3. Antyhypertensiv virkning på spontant hypertone rotter. Forbindelserne indgaves oralt til grupper på 8 han-, 25 spontant hypertone Okanoto-rotter (vægt: 280 - 350 g).3. Antihypertensive effect on spontaneously hypertonic rats. The compounds are administered orally to groups of 8 male, 25 spontaneously hypertonic Okanoto rats (weight: 280 - 350 g).
Før og 2 timer efter tilførselen måles det systoliske blodtryk på rottehalen ublodigt ved hjælp af piezokry-staloptagere.Before and 2 hours after administration, the systolic blood pressure on the rat tail is measured unsteadily by piezocrystals.
Som ED 20% bestemmes under hensyn til værdien af ube-30 handlede kontroller den dosis, som sænker det systoliske tryk med 20%.As ED 20%, taking into account the value of untreated controls, the dose that lowers systolic pressure by 20% is determined.
150602 10 4* Akut toxicitet på mus.Acute toxicity in mice.
Til bestemmelse af den akute toxicitet (LD 50) indgives forbindelsen til grupper på 10 hun NMRI-mus (vægt 19-20 g) intraperitonealt. Undersøgelsestiaen androg 1 uge.To determine the acute toxicity (LD 50), the compound is administered intraperitoneally to groups of 10 female NMRI mice (weight 19-20 g). The study path was 1 week.
5 Beregningen af de virksomme doser (metode 1-3) skete ud fra regressionsanalyse af det lineære forhold mellem logaritmen til dosis og virkningen. LD 50 (metode 4) bestemtes ved hjælp af probit-analyse. Som referenceforbindelse anvendtes det kendte β-sympatholytikum propra-10 nolol.5 The calculation of the effective doses (methods 1-3) was based on regression analysis of the linear relationship between the dose logarithm and the effect. LD 50 (Method 4) was determined by probit analysis. As the reference compound, the known β-sympatholytic propanolol was used.
Som det fremgår af tabel 1, er den β-sympatholytiske virkning fra forbindelserne i eksempel 1, 3, 6 og 13 6,1 til 20 gange højere end virkningen af det kendte β-sympatholytikum propranolol. Forbindelsen fra eksempel 15 5 er nogenlunde lig propranololens virkning.As shown in Table 1, the β-sympatholytic effect of the compounds of Examples 1, 3, 6 and 13 is 6.1 to 20 times higher than that of the known β-sympatholytic propranolol. The compound of Example 15 is approximately equal to the effect of propranolol.
Udover denne virkning sker der med de omhandlede forbindelser en akut sænkning af det arterielle blodtryk.In addition to this effect, the compounds of this invention cause an acute lowering of arterial blood pressure.
Efter tilførsel af 0,4 mg/kg fra eksempel 3 ses på rotten en blodtryksænkning på gennemsnitlig 20%. På 20 samme måde sænker forbindelserne fra eksempel 1, 5, 6 og 13 blodtrykket i doser på mellem 0,65 og 1 mg/kg (ED 20%). Propranolol virker i modsætning hertil blodtryksforøgende på rotter indtil doser fra 2,15 mg/kg.After administration of 0.4 mg / kg of Example 3, a blood pressure drop of 20% is seen on average in the rat. Similarly, the compounds of Examples 1, 5, 6 and 13 lower blood pressure at doses between 0.65 and 1 mg / kg (ED 20%). In contrast, propranolol acts to increase blood pressure in rats up to doses of 2.15 mg / kg.
Først den subletale dosis 4,64 mg/kg sænker trykket med 25 gennemsnitlig 36%. Cirka den dobbelte dosis (10 mg/kg) dræber 2 ud af 6 dyr. Efter tilførsel af 10 mg/kg af forbindelsen fra eksempel 6 dør 1 ud af 6 dyr. Denne dosis er imidlertid 25 gange større end den blodtryksænkende dosis (0,4 mg/kg).First, the sublethal dose 4.64 mg / kg lowers the pressure by an average of 36%. About twice the dose (10 mg / kg) kills 2 out of 6 animals. After administration of 10 mg / kg of the compound of Example 6, 1 in 6 animals dies. However, this dose is 25 times greater than the blood pressure lowering dose (0.4 mg / kg).
30 Som i eksempel 3 påvistes det, at forbindelserne også virker blodtryksænkende efter peroral tilførsel på spontant hypertone rotter. 14,5 mg/kg sænker forhøjede blodtryk med gennemsnitlig 20%. Propranolol er i dette forsøg 11 150602 virkningsløs indtil en dosis på 100 mg/kg.As in Example 3, it was shown that the compounds also act to lower blood pressure after oral administration in spontaneously hypertonic rats. 14.5 mg / kg lowers elevated blood pressure by an average of 20%. In this experiment, propranolol is ineffective until a dose of 100 mg / kg.
Den letale dosis (LD 50, mus, intraperitonealt) af forbindelsen fra eksempel 3 (123 mg/kg) ligger noget højere, fra eksempel 13 er den letale dosis mere end dobbelt så 5 høj som propranololets letale dosis (108 mg/kg). For bindelserne fra eksempel 1, 5 og 6 er lige så toxiske og noget mere toxiske end propranolol. I betragtning af den høje aktivitet (eksempel 1 og 6) eller den alt i alt nye virkningstype er dette fund uden relevans.The lethal dose (LD 50, mouse, intraperitoneal) of the compound of Example 3 (123 mg / kg) is somewhat higher, from Example 13 the lethal dose is more than twice the lethal dose of propranolol (108 mg / kg). For the compounds of Examples 1, 5 and 6 are just as toxic and somewhat more toxic than propranolol. Given the high activity (Examples 1 and 6) or the all new effect type, this finding is irrelevant.
10 TABEL 1TABLE 1
Eks. β-sympatholytisk Blodtryksænkende nr. virkning 1) virkning 2) Letalitet 4) _ED 50 % R.W._ED 20 %_LD 50 1 0,0077 14,3 ( 0,65 108 15 3 0,0055 20,0 0,40 123 5 0,12 0,9 0,83 95 6 0,018 6,1 0,93 84 13 0,017 6,5 1,00 247Ex. β-sympatholytic Blood pressure lowering No. effect 1) effect 2) Lethality 4) _ED 50% RW_ED 20% _LD 50 1 0.0077 14.3 (0.65 108 15 3 0.0055 20.0 0.40 123 5 0 , 12 0.9 0.83 95 6 0.018 6.1 0.93 84 13 0.017 6.5 1.00 247
Propranolol 0,11 1,0 3) 108 20 1) Katte. Hexobarbital-narkose. Applikation: intravenøs.Propranolol 0.11 1.0 3) 108 20 1) Cats. Hexobarbital anesthesia. Application: intravenous.
ED 50 % = Dosis mg/kg, som hæmmer stigningen i hjertefrekvens ved isoproterenol med 50 %. R.W. = relativ virkning. Propranolol =1,00.ED 50% = Dose mg / kg, which inhibits the increase in heart rate of isoproterenol by 50%. R.W. = relative effect. Propranolol = 1.00.
2) Rotter. Urethan-narkose. Applikation: intravenøs.2) Rats. Urethane anesthesia. Application: intravenous.
25 ED 20 % = Dosis mg/kg, der sænker blodtrykket med 20 %.25 ED 20% = Dose mg / kg lowering blood pressure by 20%.
3) Indtil 2,15 mg/kg blodtrykstigning (11 %); 4,64 mg/kg blodtryksænkning (36 %); 10 mg/kg 2/6 dyr dør.3) Up to 2.15 mg / kg blood pressure rise (11%); 4.64 mg / kg blood pressure lowering (36%); 10 mg / kg 2/6 animals die.
4) Mus. Indgivelse: intraperitoneal LD 50 (mg/kg) 12 150602 På grund af deres virkning skal særligt følgende forbindelser fremhæves: 3-methyl-5-[2-(2-hydroxy-3-isopropylamino-propoxy)-styryl]-isoxazol, smp. 106-108 °C ; 5 3-methyl-5-[2-(2-hydroxy-3-tert.-butylamino-propoxy)-styryl]- isoxazol, smp. 83-85 °C; 3-ethyl-5-[2-(2-hydroxy-3-tert.-butylamino-propoxy)-styryl]-isoxazol, smp. 163-164 °C; 3-ethyl-5-[2-(2-hydroxy-3-cyclopropylamino-propoxy)-styryl]-4) Mouse. Administration: Intraperitoneal LD 50 (mg / kg) 12 Due to their action, the following compounds in particular should be highlighted: 3-methyl-5- [2- (2-hydroxy-3-isopropylamino-propoxy) -styryl] -isoxazole, m.p. . 106-108 ° C; 3-methyl-5- [2- (2-hydroxy-3-tert.-butylamino-propoxy) -styryl] -isoxazole, m.p. 83-85 ° C; 3-Ethyl-5- [2- (2-hydroxy-3-tert.-butylamino-propoxy) -styryl] -isoxazole, m.p. 163-164 ° C; 3-ethyl-5- [2- (2-hydroxy-3-cyclopropylamino-propoxy) -styryl] -
10 isoxazol, smp. 137-139 °CIsoxazole, m.p. 137-139 ° C
3-methyl-5-[2-(2-hydroxy-3-(3-methyl-l-butyn-3-ylamino)-propoxy-styryl]-isoxazol , smp. 191 °C.3-methyl-5- [2- (2-hydroxy-3- (3-methyl-1-butyn-3-ylamino) -propoxy-styryl] -isoxazole, mp 191 ° C.
Fremgangsmåden ifølge opfindelsen forklares nærmere i de følgende udførelseseksempler.The process according to the invention is further explained in the following embodiments.
22 Fremstilling af forprodukter.22 Manufacture of Pre-Products.
Forbindelse I: o-(α-methoxy-ethoxy)-benzaldehyd.Compound I: o- (α-Methoxy-ethoxy) -benzaldehyde.
a) 610 g (5 mol) salicylaldehyd opløses i 1,5 liter xylen.a) 610 g (5 moles) of salicylaldehyde are dissolved in 1.5 liters of xylene.
Til denne opløsning sættes dråbevis ved 40 - 50°C 900 g (5 mol) af en 30 procentig NaOCHg-opløsning i methanol.To this solution is added dropwise at 40 - 50 ° C 900 g (5 moles) of a 30% NaOCH 2 solution in methanol.
20 Herefter opvarmes, og methanolen afdestilleres, som efter hånden erstattes i reaktionskolben med den samme mængde xylen. Man opvarmer så længe, indtil xylenen begynder at afdestillere (ca. 130°C ved destillationsover-gangen). Herefter afkøles suspensionen af natriumsaltet 25 af salicylaldehydet til 60°C, cg aer omsættes videre så ledes som beskrevet under c).20 is then heated and the methanol is distilled off, which is gradually replaced in the reaction flask with the same amount of xylene. It is heated for as long as the xylene begins to distill off (about 130 ° C at the distillation transition). Thereafter, the suspension of the sodium salt 25 of the salicylaldehyde is cooled to 60 ° C, and air is further reacted as directed under c).
b) 200 ml xylen tilsættes en spatelspids hydroquinon, og der afkøles til -20 til -30°C, og 290 g (5 mol) vinyl-methylether tilsættes. Herefter tilledes ved -30°Cb) 200 ml of xylene is added to a spatula tip of hydroquinone and cooled to -20 to -30 ° C and 290 g (5 moles) of vinyl methyl ether are added. Then, at -30 ° C
3Q 183 g (5 mol) HC1, og opløsningen henstår, idet tempera turen herved stiger til stuetemperatur. Opløsningen af det opnåede 1-chlorethyl-methylether omsættes videre således som beskrevet under c).3Q 183 g (5 moles) of HCl, and the solution is allowed to rise as the temperature rises to room temperature. The solution of the obtained 1-chloroethyl methyl ether is further reacted as described under c).
150602 13 c) Den under punkt b) beskrevne fremstillede opløsning af 1-chlorethylmethylether dryppes til den 60°C varme opløsning af natriumsaltet af salicylaldehyd (se under punkt a), og der omrøres yderligere i 1,5 timer 5 ved 60°C, eventuelt indstilles til en pH-værdi på 8 - 9 ved hjælp af 30 procentig NaOCH-j-op løsning, og der omrøres natten over ved stuetemperatur.C) The solution of 1-chloroethyl methyl ether described in point (b) is dripped to the 60 ° C hot solution of the sodium salt of salicylaldehyde (see point a), and further stirred for 1.5 hours at 60 ° C, optionally adjusted to a pH of 8 - 9 using 30% NaOCH-j solution and stirred overnight at room temperature.
Herefter frafiltreres det udfældede natriumchlorid, der vaskes efter med xylen, og xylenen afdampes på en 10 rotationsfordamper. Den tilbageblevne remanens destil leres over en kolonne ved 2 mmHg. Man får 690 g o-(a-methoxyethoxy)-benzaldehyd med Kp2: 94 - 96°C.Then, the precipitated sodium chloride which is washed with xylene is filtered off and the xylene is evaporated on a rotary evaporator. The residue of the residue is distilled over a column at 2 mmHg. 690 g of o- (α-methoxyethoxy) -benzaldehyde are obtained with Kp2: 94-96 ° C.
Forbindelse II: (3-methylisoxazolyl-5)-methanphosphonsyre- diethylester 445 g 5-chlormethyl-3-methylisoxazol og 674 g phosphored- 15 dikesyretriethylester opvarmes langsomt til 150°C, og man holder opløsningen ved denne temperatur i 4 timer. Efter destillation får man 546 g (69 S af den teoretiske værdi) (3-methylisoxazolyl-5-)-methanphosphonsyrediethylester med kogepunkt 118 - 121°C/0,3 Torr.Compound II: (3-Methylisoxazolyl-5) -methane phosphonic acid diethyl ester 445 g of 5-chloromethyl-3-methylisoxazole and 674 g of phosphoracetic acid triethyl ester are slowly heated to 150 ° C and the solution is kept at this temperature for 4 hours. After distillation, 546 g (69 S of theoretical value) (3-methylisoxazolyl-5 -) - methane phosphonic acid diethyl ester with boiling point 118 - 121 ° C / 0.3 Torr are obtained.
20 H-NMR-spektrum (CHC13, TMS intern): T- 3,85 (d, J = 3 Hz, IH) 4,17 (m, J = 8 Hz, 4H) 6,67 (d, J = 22 Hz, 2H) 7,72 (s, 3H) 25 8,67 (t, J = 8 Hz, 6H).1 H NMR Spectrum (CHCl 3, TMS internal): T-3.85 (d, J = 3 Hz, 1H) 4.17 (m, J = 8 Hz, 4H) 6.67 (d, J = 22 Hz, 2H) 7.72 (s, 3H) 8.67 (t, J = 8 Hz, 6H).
C9H16N04P (233,21)C9H16NO4P (233.21)
Beregnet: C 46,35 - H 6,91 - N 6,01 - P 13,28Calculated: C 46.35 - H 6.91 - N 6.01 - P 13.28
Fundet : C 45,9 - H 7,0 - N 6,0 - P 13,0.Found: C 45.9 - H 7.0 - N 6.0 - P 13.0.
Forbindelse III: (3-ethylisoxazolyl-5)-methanphosphonsyre- diethylester 3Q 15 g 5-chlormethyl-3-ethyl-isoxazol og 18 g triethylphosphit nmarmoc lanrtonmf fi 1 15fi®P_ ner Vil anrl ΐ η<-Γί»η hpnsfår 1 2.5 14 150602 manensen under formindsket tryk. Man får 18,2 g (3-ethyl-isoxazolyl-5)-methanphosphonsyrediethylester med kogepunkt 120 - 121°C/0,2 mmHg (udbytte 71,2 %) .Compound III: (3-Ethylisoxazolyl-5) -methane phosphonic acid diethyl ester 3Q 15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethylphosphite nmarmoclantronmf fi 1 15fi®P_ner 14 150602 under reduced pressure. 18.2 g (3-ethyl-isoxazolyl-5) -methane phosphonic acid diethyl ester with boiling point 120 - 121 ° C / 0.2 mmHg (yield 71.2%) are obtained.
^H-NMR-spektrum (CDCI3, TMS intern): 5 T= 3,85 (d, J = 3 Hz, IH), 4,17 '(m, J = Hz, 4H), 6,60 (d, H = 20 Hz, 2H), 7,35 (q, J = Hz, 2H), 8,50 - 8,93 (m, 9H).1 H NMR Spectrum (CDCl 3, TMS internal): δ T = 3.85 (d, J = 3 Hz, 1H), 4.17 '(m, J = Hz, 4H), 6.60 (d, H = 20 Hz, 2H), 7.35 (q, J = Hz, 2H), 8.50 - 8.93 (m, 9H).
10 C10H18NO4P (247#23)10 C10H18NO4P (247 # 23)
Beregnet: C 48,58 - H 7,34 - N 5,67 - P 12,53Calculated: C 48.58 - H 7.34 - N 5.67 - P 12.53
Fundet : C 48,4 - H 7,1 - N 5,7 - P 12,3.Found: C 48.4 - H 7.1 - N 5.7 - P 12.3.
De øvrige phosphonestere fremstilledes på analog måde.The other phosphone esters were prepared in an analogous manner.
(3-isopropyl-isoxazolyl-5)-methanphosphonsyrediethylester 15 Kpg H7 “ 122°C. Udbytte 73%.(3-isopropyl-isoxazolyl-5) -methane phosphonic acid diethyl ester 15 Kpg H7 “122 ° C. Yield 73%.
(3-tert.-butyl-isoxazolyl-5)-methanphosphonsyrediethylester KpQ 3: 126 - 132°C. Udbytte 88%.(3-tert.-butyl-isoxazolyl-5) -methane phosphonic acid diethyl ester KpQ 3: 126-132 ° C. Yield 88%.
Fremstilling af udgangsforbindelserne.Preparation of the starting compounds.
EKSEMPEL IEXAMPLE I
2 0 3 "methyl-5 2-hydroxy-s tyryl^-isoxazol 8,8 g (0,2 mol) 55% natriumhydridsuspension i paraffinolie anbringes i 100 ml absolut dimethylsulfoxid. Hertil dryppes 47 g (0,2 mol) diethyl-(3-methylisoxazolyl-5)-methylen-phosphonat ved stuetemperatur. Man omrører i yderligere 30 25 minutter, og derefter tildryppes under omrøring 36 g (0,2 mol) o-(l-methoxyethoxy)benzaldehyd, hvorefter man lader reaktionsblandingen omrøre ved stuetemperatur i 24 timer.20.8 g (0.2 mole) of 55% sodium hydride suspension in paraffin oil are placed in 100 ml of absolute dimethyl sulfoxide. To this, 47 g (0.2 mole) (3-methylisoxazolyl-5) -methylene phosphonate at room temperature is stirred for an additional 30 minutes, then 36 g (0.2 mole) of o- (1-methoxyethoxy) benzaldehyde is added dropwise, then the reaction mixture is allowed to stir at room temperature for 24 hours.
Man tilsætter 1 liter isvand, og der ekstraheres tre gange med 80 ml methylenchlorid pr. gang. De forenede organiske 150602 15 faser tørres over natriumsulfat, og der inddampes på rotationsinddamper. Den olieagtige remanens opløses i 80 ml methanol og 10 ml vand, og der tilsættes 2 ml 5 U HC1, hvorefter man omrører i yderligere 10 minutter. Herefter 5 tilsættes langsomt et overskud af vand til blandingen, indtil der udfælder et bundfald. Dette frasuges, vaskes med vand og omkrystalliseres med ethanol. 19 g (47% af det teoretiske udbytte) af farveløse krystaller med smeltepunkt 236 - 238°C.One liter of ice water is added and extracted three times with 80 ml of methylene chloride per ml. walk. The combined organic phases are dried over sodium sulfate and evaporated on rotary evaporator. Dissolve the oily residue in 80 ml of methanol and 10 ml of water and add 2 ml of 5 U HCl and stir for a further 10 minutes. Then excess 5 of water is slowly added to the mixture until a precipitate precipitates. This is extracted, washed with water and recrystallized from ethanol. 19 g (47% of theoretical yield) of colorless crystals, mp 236 - 238 ° C.
10 C12H11N02 (201)C12H11N02 (201)
Beregnet: C 71,6 - H5,5 - N 7,0Calculated: C 71.6 - H5.5 - N 7.0
Fundet : C 71,8 - H 5,5 - N 6,8Found: C 71.8 - H 5.5 - N 6.8
EKSEMPEL· IIEXAMPLE · II
3-ethyl-52i2-hydroxy-styryl)_-isoxazol 15 Som i eksempel I omsættes 6 g (0,02 mol) diethyl-(3-ethyl-isoxazolyl-5)-methylenphosphonat og 4,4 g (0,02 mol) o-(l-methoxyethoxy)-benzaldehyd, og der omkrystalliseres med iso-propanol, hvorved man får 1,7 g (32% af det teoretiske udbytte) farveløse krystaller.3-Ethyl-52 (2-hydroxy-styryl) -isoxazole As in Example 1, 6 g (0.02 mole) of diethyl (3-ethyl-isoxazolyl-5) methylene phosphonate are reacted and 4.4 g (0.02 mole) ) o- (1-methoxyethoxy) -benzaldehyde and recrystallized from iso-propanol to give 1.7 g (32% of theory) of colorless crystals.
- 20 Smeltepunkt: 175 - 176°C.Melting point: 175 - 176 ° C.
C13H13N02 (215)C13H13N02 (215)
Beregnet: C 72,5 - H6,l - N 6,5Calculated: C 72.5 - H6, l - N 6.5
Fundet : C 72,5 - H6,2 - N 6,6.Found: C 72.5 - H6.2 - N 6.6.
EKSEMPEL· IIIEXAMPLE · III
2 5 ^-isoprgpy1-5-12-hydroxy-styryiizisgxazol2 5 -isoprgpy1-5-12-hydroxy-styryizisgxazole
Som i eksempel I omsættes 32 g (0,12 mol) diethyl-(3-iso-propyl-isoxazolyl-5-)-methylen-phosphonat og 22 g (0,12 mol) o-(1-methoxyethoxy)-benzaldehyd, og der omkrystalliseres med toluen. Der fås 20 g (73% af det teoretiske 30 udbytte) farveløse krystaller.As in Example I, 32 g (0.12 mol) of diethyl (3-iso-propyl-isoxazolyl-5-) -methylene phosphonate and 22 g (0.12 mol) of o- (1-methoxyethoxy) -benzaldehyde are reacted. and recrystallized from toluene. 20 g (73% of theory 30 yield) of colorless crystals are obtained.
Smeltepunkt: 129 - 133°C.Melting point: 129 - 133 ° C.
150602 16 C16H15N02 (229)150602 16 C16H15N02 (229)
Beregnet: C 73,3 - Η 6,6 - Ν 6,1Calculated: C 73.3 - Η 6.6 - Ν 6.1
Fundet : C 73,7 - Η 6,7 - H 5,8.Found: C 73.7 - Η 6.7 - H 5.8.
EKSEMPEL IVEXAMPLE IV
5 ^itert^-butYl-S^ U-hYdroxY-stYrYl)_-isoxazol5-iterated-butyl-S ^ U-hydroxy-styryl) -isoxazole
Der omsættes som i eksempel I 35 g (0,13 mol) diethyl-iltert. -butyl-isoxazolyl-5)-methylen-phosphonat og 23 g (0,13 mol) o-(1-methoxyethoxy)-benzaldehyd, og man omkrystalliserer med toluen. Der fås 24,8 g (78 % af teoretisk udbytte) af 10 farveløse krystaller.35 g (0.13 mole) of diethyl ether is reacted as in Example I. -butyl-isoxazolyl-5) -methylene phosphonate and 23 g (0.13 mol) of o- (1-methoxyethoxy) -benzaldehyde and recrystallized from toluene. 24.8 g (78% of theoretical yield) of 10 colorless crystals are obtained.
Smeltepunkt: 152 - 155°C.Melting point: 152 - 155 ° C.
C15H17N02 ^243)C15H17NO2 (243)
Beregnet: C 74,0 - H 7,0 - N 5,8Calculated: C 74.0 - H 7.0 - N 5.8
Fundet : C 73,4 - H 7,3 - N 5,5.Found: C 73.4 - H 7.3 - N 5.5.
15 EKSEMPEL VEXAMPLE V
llSSt^Yll^lI^ii^iS-epoxyprogoxy^-stYrYjJ-isoxazol 6,44 g 55 procentig natriumhydrid i paraffinolie (0,15 mol) anbringes i 200 ml absolut dimethylsulfoxid, og der tilsættes dråbevis ved stuetemperatur 30 g (0,15 mol) 3-methyl-5-(2-20 hydroxy-styryl)-isoxazol opløst i 50 ml dimethylsulfoxid.11St ^ Yll ^ lI ^ ii ^ iS-epoxyprogoxy ^ -styrYjJ -isoxazole 6.44 g of 55% sodium hydride in paraffin oil (0.15 mol) is placed in 200 ml of absolute dimethyl sulphoxide and added dropwise at room temperature 30 g (0.15 mole) 3-methyl-5- (2-20 hydroxy-styryl) -isoxazole dissolved in 50 ml of dimethyl sulfoxide.
Efter at hydrogenudviklingen er ophørt, tildryppes 20,2 g (0,15 mol) epibromhydrin, og reaktionsblandingen omrøres i 20 timer ved stuetemperatur. Blandingen tilsættes 1,5 liter isvand, og den faste remanens frasuges og omkrystalliseres af 25 isopropanol. Der fås 26,2 g (68% af det teoretiske udbytte) af farveløse krystaller.After hydrogen evolution has ceased, 20.2 g (0.15 mole) of epibromohydrin is added dropwise and the reaction mixture is stirred for 20 hours at room temperature. The mixture is added 1.5 liters of ice water and the solid residue is suctioned off and recrystallized from 25 isopropanol. 26.2 g (68% of theoretical yield) of colorless crystals are obtained.
Smeltepunkt: 99 - 100°C.Melting point: 99-100 ° C.
C15H15N03 <257)C15H15N03 <257)
Beregnet: C 70,0 - H 5,9 - N 5,4 30 Fundet : C 70,0 - H 5,9 - N 5,5.Calculated: C 70.0 - H 5.9 - N 5.4 Found: C 70.0 - H 5.9 - N 5.5.
EKSEMPEL VIEXAMPLE VI
17 150602 3-θ^γ1-5-^2-_(2χ3-βροχγρΓθροχγ)_23ΐγΓγ1]_-ΐ3θΧ§ζο117 150602 3-θ ^ γ1-5- ^ 2 -_ (2χ3-βροχγρΓθροχγ) _23ΐγΓγ1] _- ΐ3θΧ§ζο1
Forbindelsen fremstilles analogt med V ud fra 5,1 g 55 pro-centig natriumhydrid (0,116 mol), 25,0 g (0,116 mol) 3-5 ethyl-5-(2-hydroxystyryl)-isoxazol og 15,9 g (0,116 mol) epibromhydrin. Reaktionsblandingen udhældes på kogsaltopløs ning, og der udrystes med diethylether. Den etheriske opløsning tørres med vandfrit natriumsulfat og inddampes. Man får 29,2 g (93% af det teoretiske udbytte) af en farveløs 10 olie.The compound is prepared analogously to V from 5.1 g of 55% sodium hydride (0.116 mole), 25.0 g (0.116 mole) of 3-5 ethyl 5- (2-hydroxystyryl) isoxazole and 15.9 g (0.116 mol) epibromohydrin. The reaction mixture is poured onto brine and shaken with diethyl ether. The ethereal solution is dried over anhydrous sodium sulfate and evaporated. 29.2 g (93% of theoretical yield) of a colorless oil are obtained.
EKSEMPEL VIIEXAMPLE VII
3-isoprgpYl25-J2-(2 f3-epoxyprppoxy)-styryjj-isoxazol3-Isoprgpyl 25-J2- (2β-epoxy-propoxy) -styryz-isoxazole
Fremstillet analogt med eksempel VI ud fra 3,4 g 55 procentig natriumhydrid (0,078 mol), 18 g (0,078 mol) 3-isopropyl-5-15 (2-hydroxystyryl)-isoxazol og 10,8 g (0,078 mol) epibromhy drin. Man fik 21,5 g (97% af det teoretiske udbytte) af en farveløs olie.Prepared analogously to Example VI from 3.4 g of 55% sodium hydride (0.078 mol), 18 g (0.078 mol) of 3-isopropyl-5-15 (2-hydroxystyryl) -isoxazole and 10.8 g (0.078 mol) of epibromohydrin . 21.5 g (97% of theoretical yield) of a colorless oil were obtained.
EKSEMPEL VIIIEXAMPLE VIII
^itSitil^ytYilåll^ii^iS-egoxYpropoxY^-stYrYl^-isoxazol 20 Fremstillet analogt med eksempel VI ud fra 3,8 g 55 procentig s natriumhydrid (0,086 mol), 21 g (0,086 mol) 3-tert.-butyl- 5-(2-hydroxystyryl)-isoxazol og 11,8 g (0,086 mol) epibromhydrin. Man fik 25,0 g (97% af det teoretiske udbytte) af en farveløs olie.Prepared analogously to Example VI from 3.8 g of 55 percent sodium hydride (0.086 mole), 21 g (0.086 mole) of 3-tert.-butyl-1-yl. 5- (2-hydroxystyryl) -isoxazole and 11.8 g (0.086 mole) of epibromohydrin. 25.0 g (97% of theoretical yield) of a colorless oil were obtained.
25 EKSEMPEL IXEXAMPLE IX
1,0 g 3-methy1-5-[2-(2,3-epoxypropoxy)styryl]-isoxazol opløses i 20 ml 3-N-etherisk hydrogenchloridopløsning, og blandingen henstår 12 timer ved stuetemperatur.1.0 g of 3-methyl-5- [2- (2,3-epoxypropoxy) styryl] -isoxazole is dissolved in 20 ml of 3-N-ethereal hydrogen chloride solution and the mixture is allowed to stand for 12 hours at room temperature.
Den dannede harpiksagtige del fraskilles og kromatograferes 30 med chloroform over kiselgel. Produkteluatet inddampes til tørhed i vakuum, og det herved fremkomne råudtræk omkrystalliseres af en acetone-cyclohexanblanding. Man får 150602 18 NMR-spektroskopisk rent (3-methyl-5-[2-(2-hydroxy-3-chlor-propoxy)-styryl]-isoxazol med smeltepunktet 67 - 68°C.The resinous portion formed is separated and chromatographed with chloroform over silica gel. The product eluate is evaporated to dryness in vacuo and the resulting crude extract is recrystallized from an acetone-cyclohexane mixture. NMR spectroscopically pure (3-methyl-5- [2- (2-hydroxy-3-chloro-propoxy) -styryl) -isoxazole) is obtained, m.p. 67-68 ° C.
^H-NMR-spektrum (CDCl^, TMS intern) .1 H-NMR spectrum (CDCl3, TMS internal).
2,30, 3,15 (m, 6H) 5 3r92 (s, 1H) 5/60-5,92 (m, 3H) 6,24 (d, J = 3,5 Hz, 2H) 6,77 (bredt s, OH).2.30, 3.15 (m, 6H) δ 3r92 (s, 1H) 5 / 60-5.92 (m, 3H) 6.24 (d, J = 3.5 Hz, 2H) 6.77 ( wide s, OH).
Fremstilling af de omhandlede forbindelser: 10 EKSEMPEL 1 3lii}§thyl-52_[2-j(2-hydroxy-3-isopro2yl-airiinogropgxy)_-styryl]_- isoxazol 3,4 g (0,013 mol) 3-methyl-5-[2-(2,3-epoxy-propoxy)-styryl]-isoxazol og 2,3 g (0,039 mol) isopropylamin opvarmes med 15 tilbagesvaling i 8 timer i 50 ml isopropanol. Efter afkøling filtreres reaktionsopløsningen, og der inddampes på rotationsinddamper. Man får 3,8 g fast remanens, der omkrystalliseres med toluen. Der fås 2,4 g (58% af det teoretiske udbytte) af farveløse krystaller.Preparation of the compounds of the invention: EXAMPLE 1 3 III 1-Ethyl-52 [2-j (2-hydroxy-3-isopro2yl-airinogropoxy) -styryl] -isoxazole 3.4 g (0.013 mol) 3-methyl-5 - [2- (2,3-epoxy-propoxy) -styryl] -isoxazole and 2.3 g (0.039 mol) of isopropylamine are heated at reflux for 8 hours in 50 ml of isopropanol. After cooling, the reaction solution is filtered and evaporated on rotary evaporator. 3.8 g of solid residue are obtained which are recrystallized from toluene. 2.4 g (58% of theoretical yield) of colorless crystals are obtained.
20 Smeltepunkt: 106 - 108°C.Melting point: 106 - 108 ° C.
C18H24H2°3 (316'4)C18H24H2 ° 3 (316'4)
Beregnet: C 68,3 - H 7,6 - N 8,9Calculated: C 68.3 - H 7.6 - N 8.9
Fundet : C 68,4 - H 7,6 - N 9,0.Found: C 68.4 - H 7.6 - N 9.0.
EKSEMPEL 2 25 3-methyl-5-J[2-_(2-hydroxy-3-cycloprogylarciinopropoxy)_-styryl]_3 isoxazol_EXAMPLE 2 3-Methyl-5-J [2- (2-hydroxy-3-cycloprogylarciinopropoxy) _-styryl] -3 isoxazole
Fremstillet analogt med eksempel 1 ud fra 5,0 g (0,019 mol) 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazol og 1,21 g (0,2 mol) cyclopropylamin. Ud fra toluen får man 2,4 g (40% 30 af det teoretiske udbytte) af farveløse krystaller med smel- 150802 19 tepunkt 108 - 109°C.Prepared analogously to Example 1 from 5.0 g (0.019 mole) of 3-methyl-5- [2- (2,3-epoxypropoxy) -styryl] isoxazole and 1.21 g (0.2 mole) of cyclopropylamine. From toluene 2.4 g (40% 30 of theoretical yield) of colorless crystals with melting point 108 DEG-109 DEG C. are obtained.
C18H22N2°3 (314/4)C18H22N2 ° 3 (314/4)
Beregnet: C 68,8 - H 7,1 - N 8,9Calculated: C 68.8 - H 7.1 - N 8.9
Fundet : C 6 8,8 ~ H 7,0 ~ N 8,9.Found: C 6 8.8 ~ H 7.0 ~ N 8.9.
5 EKSEMPEL 3 ^iS^i'hxilSlI^li^hydroxY^S-tert^-butylaminogrogoxy) -styryl] -isoxazolEXAMPLE 3 (iS ^ i'hxilSlIl (hydroxyl) S-tert-butylaminogrogoxy) -styryl] -isoxazole
Fremstillet analogt med eksempel 1 ud fra 5,0 g (0,019 mol) 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazol og 1,56 10 g (0,2 mol) tert.-butylamin.Prepared analogously to Example 1 from 5.0 g (0.019 mole) of 3-methyl-5- [2- (2,3-epoxypropoxy) -styryl] isoxazole and 1.56 g (0.2 mole) of tert. -butylamine.
3,1 g (48% af det teoretiske udbytte) af farveløse krystaller med smeltepunkt 83 - 85°C) C19H27N2°3 ' °'5 H2° <339'4>3.1 g (48% of theoretical yield) of colorless crystals, mp 83-85 ° C) C19H27N2 ° 3 '°' 5 H2 ° <339'4>
Beregnet: C 67,3 - H 8,0 - N 8,3 15 Fundet : C 67,2 - H 7,9 - N 8,1.Calculated: C 67.3 - H 8.0 - N 8.3 Found: C 67.2 - H 7.9 - N 8.1.
30 g råt 3-methyl-5-[2-(2-hydroxy-3-tert.-butylaminopropoxy)-styryl]isoxazol opløses i lidt ethanol, og tilsættes indtil fuldstændig udfældning dråbevis etherisk hydrogenchloridop-løsning. Det udfældede 3-methyl-5-[2-(2-hydroxy-3-tert.-20 butylaminopropoxy)-styryl]-isoxazol-hydrochlorid frasuges, der vaskes med tør ether og omkrystalliseres to gange med methanol-ether-blanding (rumfang 1:1) og tørres.30 g of crude 3-methyl-5- [2- (2-hydroxy-3-tert.-butylaminopropoxy) -styryl] isoxazole are dissolved in a little ethanol and added dropwise to ethereal hydrogen chloride solution dropwise. The precipitated 3-methyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) -styryl] -isoxazole hydrochloride is suction washed, washed with dry ether and recrystallized twice with methanol-ether mixture (volume). 1: 1) and dried.
Udbytte 33,8 g (79% af det teoretiske udbytte) med smeltepunkt 217°C.Yield 33.8 g (79% of theory), mp 217 ° C.
25 C19H2703N2C1 (367)C19H2703N2C1 (367)
Beregnet: C 62,2 - H 7,4 - N 7,6 - Cl 9,7Calculated: C 62.2 - H 7.4 - N 7.6 - Cl 9.7
Fundet : C 62,1 - H 7,3 - N 7,7 - Cl 9,8.Found: C 62.1 - H 7.3 - N 7.7 - Cl 9.8.
På samme måde fås med etherisk fumarsyre fumaratet med EKSEMPEL 4 20 150602 smeltepunktet 188°C.Similarly, with the ethereal fumaric acid, the fumarate of EXAMPLE 4 is obtained, m.p. 188 ° C.
3iethYl-M2-j2-hYdroxY=3-iso2ro2Ylamino2ro2oxY)_stYrYl]_- isoxazol 5 Fremstilles ud fra 7 g (0,026 mol) 3-ethyl-5-[2-(2,3-epoxy-propoxy)styryl]-isoxazol og 2f4 g isopropylamin (0,04 mol) i 100 ml isopropanol. Man får 8,1 g af en olie, der opløses i 100 ml isopropanol og tilsættes etherisk saltsyre. De udfældede krystaller frasuges og tørres.3iethyl-M2-j2-hydroxy = 3-iso2ro2ylamino2roxyoxyl) styryl] -isoxazole 5 Prepared from 7 g (0.026 mol) of 3-ethyl-5- [2- (2,3-epoxy-propoxy) styryl] -isoxazole and 2 µg of isopropylamine (0.04 mol) in 100 ml of isopropanol. 8.1 g of an oil are dissolved in 100 ml of isopropanol and ethereal hydrochloric acid is added. The precipitated crystals are aspirated and dried.
10 4,9 g (50% af det teoretiske udbytte) med smeltepunkt 134 - 135°C.4.9 g (50% of theoretical yield), mp 134-135 ° C.
C19H25C1N2°3 (366,9)C19H25ClN2 ° 3 (366.9)
Beregnet: C 62,7 - H 7,4 - N 7,6 - Cl 9,7 Fundet : C 61,9 - H 6,9 - N 7,7 - Cl 9,6.Calculated: C 62.7 - H 7.4 - N 7.6 - Cl 9.7 Found: C 61.9 - H 6.9 - N 7.7 - Cl 9.6.
15 EKSEMPEL 5 3rgthyl-512-(2-hYdroxy-3-cyclopropylaminopropoxy)-styryll-isoxazol_ 7 g (0,026 mol) 3-ethyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazol og 2,3 g cyclopropylamin (0,04 mol) omsættes ana-20 logt med eksempel 1 i 100 ml isopropanol. Man får 8,6 g af en olie, der skilles på en søjle (55 x 5 cm) af kiselgel 60 (0,063 - 0,20 mm) fra Merck fabrikkerne for at fjerne forureninger. Elueringsmidlet er en 9 : 1-blanding af methylenchlorid og methanol. Fraktionerne efterprøves for 25 renhed ved tyndtlagskromatografi. Man får 3,2 g af en olie, der opløses i 40 ml isopropanol og en smule ether, og som fældes med 1,1 g fumarsyre opløst i varm isopropanol. Krystallerne frasuges og tørres.EXAMPLE 5 3-Methyl-512- (2-hydroxy-3-cyclopropylaminopropoxy) -styrryl-isoxazole-7 g (0.026 mol) 3-ethyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazole and 2, 3 g of cyclopropylamine (0.04 mol) is reacted analogously to Example 1 in 100 ml of isopropanol. 8.6 g of an oil is separated on a column (55 x 5 cm) of silica gel 60 (0.063 - 0.20 mm) from the Merck factories to remove contaminants. The eluent is a 9: 1 mixture of methylene chloride and methanol. The fractions are tested for purity by thin layer chromatography. There is obtained 3.2 g of an oil which is dissolved in 40 ml of isopropanol and a little ether, which is precipitated with 1.1 g of fumaric acid dissolved in hot isopropanol. The crystals are aspirated and dried.
2,1 g (21% af det teoretiske udbytte) med smeltepunkt 137 -30 139°C.2.1 g (21% of theoretical yield), mp 137 -30 139 ° C.
150602 21 C22H26N2°5 ί386'5)150602 21 C22H26N2 ° 5 (386'5)
Beregnet: C 65,2 - H 6,7 - N 7,2Calculated: C 65.2 - H 6.7 - N 7.2
Fundet : C 64,7 - H 6,8 - N 7,5.Found: C 64.7 - H 6.8 - N 7.5.
EKSEMPEL 6 5 3-ethyl-5- [2- (2-hydroxy-3-tert.-butylaminopropoxy) styryl]- isoxazol 7 g (0,026 mol) 3-ethy1-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazol og 3,0 g (0,04 mol) tert.-butylamin omsættes analogt med eksempel 4. 6,6 g (66% af det teoretiske udbytte) 10 med smeltepunkt 163 - 164°C.EXAMPLE 6 3-Ethyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) styryl] -isoxazole 7 g (0.026 mol) of 3-ethyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazole and 3.0 g (0.04 mole) of tert-butylamine are reacted analogously to Example 4. 6.6 g (66% of theoretical yield) 10, mp 163 - 164 ° C.
C20H29C1N2°3C20H29C1N2 ° 3
Beregnet: C 63,1 - H 7,7 - N 7,3 - Cl 9,3Calculated: C 63.1 - H 7.7 - N 7.3 - Cl 9.3
Fundet : C 62,9 - H 7,5 - N 7,2 - Cl 9,2.Found: C 62.9 - H 7.5 - N 7.2 - Cl 9.2.
EKSEMPEL 7 15 3li§2EE2EYil3li2li2l3iiY^E22Yl2li22EE2E¥i2i2i22Ei-2E25Yil§i:¥?iYill isoxaz2l 7 g (0,025 mol) 3-isopropy1-5-[2-(2,3-epoxypropoxy)styryl]-isoxazol og 3,0 g (0,05 mol) isopropylamin omsættes analogt med eksempel 1.EXAMPLE 7 3li§2EE2EYil3li2li2l3iiY ^ E22Yl2li22EE2E ¥ i2i2i22Ei-2E25Yil§i: yl yl isoxaz2l 7 g (0.025 mol) 3-isopropyl-5- [2- (2,3-epoxypropoxy) styryl] -isox] (0.05 mole) of isopropylamine is reacted analogously to Example 1.
20 Af toluen får man 5,9 g (68% af det teoretiske udbytte) af farveløse krystaller med smeltepunkt 87 - 88°C.20 of toluene 5.9 g (68% of theoretical yield) of colorless crystals having a melting point 87 - 88 ° C are obtained.
C20H28N2°3 (344'5>C20H28N2 ° 3 (344'5>
Beregnet: C 69,7 - H 8,2 - N 8,1Calculated: C 69.7 - H 8.2 - N 8.1
Fundet : C 69,9 - H 8,2 - N 8,1.Found: C 69.9 - H 8.2 - N 8.1.
EKSEMPEL 8 22 150602 ^li22E£2BYiz5~I2-j(2-hYdroxY-3-cYcloprogYlaminogro20XY)-- §tY£Yiili§22§2ol 7 g (0,025 mol) 3-isopropyl-5-[2-(2,3-epoxypropoxy)styryll-5 isoxazol og 3,0 g (0,05 mol) cyclopropylamin omsættes analogt med eksempel 5. Man får 3,0 g (30% af det teoretiske udbytte) af farveløse krystaller som fumarat med smeltepunkt 148 -152°C.EXAMPLE 8 22 (2-Hydroxy-3-cycloprogylaminogro20XY) - γTY 2 Y 2 S 22 22 S 7 g (0.025 mol) 3-isopropyl-5- [2- (2.3 epoxypropoxy) styryl-5-isoxazole and 3.0 g (0.05 mole) of cyclopropylamine are reacted analogously to Example 5. 3.0 g (30% of theoretical yield) of colorless crystals are obtained as fumarate, mp 148-152 ° C.
C22H28N2°5 (400'5) 10 Beregnet: C 66,0 - H 7,0 - H 7,0C22H28N2 ° 5 (400'5) Calculated: C 66.0 - H 7.0 - H 7.0
Fundet : C 65,7 - H6,8 - N 7,0.Found: C 65.7 - H6.8 - N 7.0.
EKSEMPEL 9 ^lisopropYl-S-^-jt^-hYdroxy-S-tertj.-butYlaminoprogoxY^- styrYll-isoxazol 15 7 g (0,025 mol) 3-isopropyl-5-[2-(2,3-epoxypropoxy)styryl]- isoxazol og 3,6 g (0,05 mol) tert.-butylamin omsættes analogt med eksempel 4. Man får 5,8 g (59 % af det teoretiske udbytte) af farveløse krystaller med et smeltepunkt på 191 -193°C.EXAMPLE 9 - Lisopropyl-S - 3 - tert -hydroxy-S-tert-butylaminoprogoxyl-styryl-isoxazole 7 g (0.025 mol) 3-isopropyl-5- [2- (2,3-epoxypropoxy) styryl] isoxazole and 3.6 g (0.05 mole) of tert-butylamine are reacted analogously to Example 4. 5.8 g (59% of theoretical yield) of colorless crystals having a melting point of 191 -193 ° C are obtained.
2° C21B31C1N203 (394,9)2 ° C21B31C1N2O3 (394.9)
Beregnet: C 63,9 - H 7,9 - N 7,1 - Cl 9,0Calculated: C 63.9 - H 7.9 - N 7.1 - Cl 9.0
Fundet : C 64,1 - H 8,0 - N 6,9 - Cl 9,1.Found: C 64.1 - H 8.0 - N 6.9 - Cl 9.1.
EKSEMPEL 10 3-tert.-buty1-5-[2-(2-hydroxy-3-isopropYlaminopropgxy)-25 styryl]_-isoxazol 7 g (0,023 mol) 3-tert.-buty1-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazol og 2,8 g (0,05 mol) isopropylamin omsættes analogt med eksempel 5. Man får 2,5 g (27% af det teoretiske udbytte) af farveløse krystaller som fumarat med smeltepunktet 30 192 - 194°C.EXAMPLE 10 3-tert.-butyl-5- [2- (2-hydroxy-3-isopropylaminopropyl) -styryl] -isoxazole 7 g (0.023 mol) of 3-tert-butyl-5 - [2- (2) , 3-Epoxypropoxy) -styryl] -isoxazole and 2.8 g (0.05 mole) of isopropylamine are reacted analogously to Example 5. 2.5 g (27% of theoretical yield) of colorless crystals are obtained as fumarate with the melting point 30 192 - 194 ° C.
150602 23 C25H34N2°5 (474'6)C25H34N2 ° 5 (474'6)
Beregnet: C 66,3 - Η 7,6 - Ν 6,7Calculated: C 66.3 - Η 7.6 - Ν 6.7
Fundet : C 66,5 - Η 7,8 - Ν 6,6.Found: C 66.5 - Η 7.8 - Ν 6.6.
EKSEMPEL 11 5 S-tert^-butYl-S-^-^g-hYdroxY-S-CYclogrogYlaininoprogoxYl- 7 g (0,023 mol) 3-tert.-butyl-5-[2-(2,3-epoxypropoxy)styryl]-isoxazol og 2,7 g (0,047 mol) cyclopropylamin omsættes analogt med eksempel 1. Man får 5,8 g olie, der opløses i di-10 ethylether, og der fældes med 2 g oxalsyre, der er opløst i lidt ethanol. Man får 2,7 g (26% af det teoretiske udbytte) af farveløse krystaller med smeltepunktet 170 - 174°c.EXAMPLE 11 5-tert-butyl-5 - 6-g-hydroxy-5-cyclogroglylininoprogoxyl-7 g (0.023 mol) 3-tert-butyl-5- [2- (2,3-epoxypropoxy) styryl] -isoxazole and 2.7 g (0.047 mol) of cyclopropylamine are reacted analogously to Example 1. 5.8 g of oil are dissolved in diethyl ether and precipitated with 2 g of oxalic acid dissolved in a little ethanol. 2.7 g (26% of theoretical yield) of colorless crystals are obtained, mp 170 - 174 ° c.
C23H30N2°7 (446'5)C23H30N2 ° 7 (446'5)
Beregnet: C 61,9 - H 6,8 - H 6,3 15 Fundet : C 62,9 - H 7,0 - N 6,2.Calculated: C 61.9 - H 6.8 - H 6.3 Found: C 62.9 - H 7.0 - N 6.2.
EKSEMPEL 12 ^Zt§iiiI^tYl-5-^2-j2-hYdroxY-3-tert_.“butYlaminopropoxY)_- 7 g (0,023 mol) 3-tert.-butyl-5-[2-(2,3-epoxypropoxy)-20 styryl]-isoxazol og 3,4 g (0,047 mol) tert.-butylamin omsættes analogt med eksempel 4. Man får 6,8 g (72% af det teoretiske udbytte) af farveløse krystaller med smeltepunktet 207 - 208°C.EXAMPLE 12-Zt-IIIl-tyl-5- [2-j2-Hydroxy-3-tert-butylaminopropoxy] -7 g (0.023 mol) 3-tert-butyl-5- [2- (2,3- epoxypropoxy-20 styryl] -isoxazole and 3.4 g (0.047 mole) of tert.-butylamine are reacted analogously to Example 4. 6.8 g (72% of theoretical yield) of colorless crystals having a melting point of 207-208 ° are obtained. C.
C22H33C11J2°3 (408'9) 25 Beregnet: C 64,6 - H 8,1 - Cl 8,7 - N 6,9C22H33C11J2 ° 3 (408'9) Calculated: C 64.6 - H 8.1 - Cl 8.7 - N 6.9
Fundet : C 64,2 - H 8,0 - Cl 8,6 - N 6,7.Found: C 64.2 - H 8.0 - Cl 8.6 - N 6.7.
EKSEMPEL 13 24 150602 3-methyl-5-j|2-(2-hydroxy-3-(3-methyl-l-butyn-3-ylamino) -propoxy)-styryl]-isoxazgl 5 g (0,019 mol) 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-5 isoxazol og 1,7 g (0,02 mol) 3-methyl-3-amino-butyn-l omsættes analogt med eksempel 3, og overføres som beskrevet i eksemplet til hydrochloridet.Example 13 24 3-Methyl-5-β-2- (2-hydroxy-3- (3-methyl-1-butyn-3-ylamino) -propoxy) -styryl] -isoxazgl 5 g (0.019 mol) methyl 5- [2- (2,3-epoxypropoxy) -styryl] -5-isoxazole and 1.7 g (0.02 mol) of 3-methyl-3-amino-butyne-1 are reacted analogously to Example 3 and transferred as described in the hydrochloride example.
Udbytte: 3,5 g (49% af det teoretiske udbytte) med smelte punkt 191°C.Yield: 3.5 g (49% of theory) with mp 191 ° C.
10 C20H25N2C1O3 (376'9)C20H25N2C1O3 (376'9)
Beregnet: C 63,7 - H 6,7 - N 7,4 - Cl 9,4Calculated: C 63.7 - H 6.7 - N 7.4 - Cl 9.4
Fundet : C 63,7 - H 6,8 - H 7,7 - Cl 9,5.Found: C 63.7 - H 6.8 - H 7.7 - Cl 9.5.
EKSEMPEL 14 3-methyl-5-[2-(2-hydroxy-3-tert.-butylaminopropoxy)-styryl]-15 i§25§2ol-hydrochloridEXAMPLE 14 3-Methyl-5- [2- (2-hydroxy-3-tert.-butylaminopropoxy) -styryl] -15
I en autoklav opvarmes 2,4 g 3-methyl-5-[2-(2-hydroxy-3-chlorpropoxy)-styryl]-isoxazol, 10 ml tert,-butylamin og 50 ml dioxan til 100°C i 10 timer. Efter afdestillation af den flygtige del i vakuum udrystes det højviskose råudtræk i 20 ether-2N svovlsyre, vandfasen indstilles forsigtigt med 4NIn an autoclave, 2.4 g of 3-methyl-5- [2- (2-hydroxy-3-chloropropoxy) -styryl] -isoxazole, 10 ml of tert, butylamine and 50 ml of dioxane are heated to 100 ° C for 10 hours. After distilling off the volatile portion in vacuo, the high viscous crude extract is shaken in 20 ether-2N sulfuric acid, the water phase is gently adjusted with 4N
natronlud, og der ekstraheres til slut med ether. Efter tørring af den organiske fase over natriumsulfat fjernes opløsningsmidlet, og den tilbageblevne remanens overføres som beskrevet i eksempel 3 i 3-methyl-5-[2-(2-hydroxy-3-tert.-25. butylaminopropoxy)-styryl]-isoxazol-hydrochlorid med smelte punkt 216 - 218°C.baking soda and finally extracted with ether. After drying the organic phase over sodium sulfate, the solvent is removed and the residue is transferred as described in Example 3 into 3-methyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) -styryl] -isoxazole hydrochloride, mp 216 - 218 ° C.
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19782818999 DE2818999A1 (en) | 1978-04-29 | 1978-04-29 | AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXYSTYRYL) -ISOXAZOLES |
DE2818999 | 1978-04-29 |
Publications (3)
Publication Number | Publication Date |
---|---|
DK175179A DK175179A (en) | 1979-10-30 |
DK150602B true DK150602B (en) | 1987-04-13 |
DK150602C DK150602C (en) | 1987-12-07 |
Family
ID=6038372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK175179A DK150602C (en) | 1978-04-29 | 1979-04-27 | METHOD OF ANALOGUE FOR PREPARING AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS |
Country Status (19)
Country | Link |
---|---|
US (1) | US4251539A (en) |
EP (1) | EP0005192B1 (en) |
JP (1) | JPS54144365A (en) |
AT (1) | AT366674B (en) |
AU (1) | AU522924B2 (en) |
CA (1) | CA1128051A (en) |
CS (1) | CS207788B2 (en) |
DD (1) | DD143257A5 (en) |
DE (2) | DE2818999A1 (en) |
DK (1) | DK150602C (en) |
ES (1) | ES480046A1 (en) |
FI (1) | FI791363A (en) |
GR (1) | GR68708B (en) |
HU (1) | HU178989B (en) |
IE (1) | IE48277B1 (en) |
IL (1) | IL57088A0 (en) |
NO (1) | NO791428L (en) |
YU (1) | YU40994B (en) |
ZA (1) | ZA792025B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2943405A1 (en) * | 1979-10-26 | 1981-05-07 | Basf Ag, 6700 Ludwigshafen | NEW AMINO DERIVATIVES OF 5- (2-HYDROXYSTYRYL) -ISOXAZOLE |
IE59813B1 (en) * | 1986-05-09 | 1994-04-06 | Warner Lambert Co | Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxy-genase inhibitors and pharmaceutical compositions containing them |
EP0691962B1 (en) * | 1993-03-29 | 2000-09-13 | Basf Aktiengesellschaft | 1-amino-3-phenoxy propane derivatives as modulators of multi-drug resistance |
JP2000512997A (en) * | 1996-06-17 | 2000-10-03 | イーライ・リリー・アンド・カンパニー | Drug resistance and multidrug resistance modulators |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH451115A (en) * | 1964-09-10 | 1968-05-15 | Ciba Geigy | Process for the preparation of a new amine |
CA945172A (en) * | 1969-02-21 | 1974-04-09 | Imperial Chemical Industries Limited | Alkanolamine derivatives |
US3836671A (en) * | 1969-02-21 | 1974-09-17 | Ici Ltd | Alkanolamine derivatives for producing beta-adrenergic blockade |
BE754405A (en) * | 1969-08-05 | 1971-02-04 | Thomae Gmbh Dr K | NEW BETA-ARYL-2-AMINOALCOXYSTYRENES |
US3624079A (en) * | 1969-10-20 | 1971-11-30 | Upjohn Co | 5-(phenylstryl)-3methylisoxazoles |
DE2624918A1 (en) * | 1976-06-03 | 1977-12-15 | Thomae Gmbh Dr K | MEDICINAL PRODUCTS WITH ANTIARRHYTHMIC EFFECT |
-
1978
- 1978-04-29 DE DE19782818999 patent/DE2818999A1/en not_active Withdrawn
-
1979
- 1979-03-16 GR GR58627A patent/GR68708B/el unknown
- 1979-04-11 EP EP79101108A patent/EP0005192B1/en not_active Expired
- 1979-04-11 CA CA325,382A patent/CA1128051A/en not_active Expired
- 1979-04-11 DE DE7979101108T patent/DE2961653D1/en not_active Expired
- 1979-04-17 IL IL57088A patent/IL57088A0/en unknown
- 1979-04-17 US US06/030,927 patent/US4251539A/en not_active Expired - Lifetime
- 1979-04-24 JP JP4991979A patent/JPS54144365A/en active Granted
- 1979-04-25 CS CS792882A patent/CS207788B2/en unknown
- 1979-04-26 DD DD79212522A patent/DD143257A5/en unknown
- 1979-04-26 FI FI791363A patent/FI791363A/en not_active Application Discontinuation
- 1979-04-27 DK DK175179A patent/DK150602C/en not_active IP Right Cessation
- 1979-04-27 ZA ZA792025A patent/ZA792025B/en unknown
- 1979-04-27 AT AT0319779A patent/AT366674B/en not_active IP Right Cessation
- 1979-04-27 HU HU79BA3778A patent/HU178989B/en not_active IP Right Cessation
- 1979-04-27 ES ES480046A patent/ES480046A1/en not_active Expired
- 1979-04-27 NO NO791428A patent/NO791428L/en unknown
- 1979-04-27 AU AU46557/79A patent/AU522924B2/en not_active Ceased
- 1979-04-27 YU YU1021/79A patent/YU40994B/en unknown
- 1979-08-08 IE IE857/79A patent/IE48277B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
DK175179A (en) | 1979-10-30 |
ATA319779A (en) | 1981-09-15 |
EP0005192B1 (en) | 1981-12-30 |
DE2818999A1 (en) | 1979-11-15 |
GR68708B (en) | 1982-02-02 |
DD143257A5 (en) | 1980-08-13 |
JPS54144365A (en) | 1979-11-10 |
ZA792025B (en) | 1980-06-25 |
IL57088A0 (en) | 1979-07-25 |
ES480046A1 (en) | 1980-09-01 |
AU4655779A (en) | 1979-11-01 |
IE790857L (en) | 1979-10-29 |
EP0005192A1 (en) | 1979-11-14 |
FI791363A (en) | 1979-10-30 |
HU178989B (en) | 1982-07-28 |
AT366674B (en) | 1982-04-26 |
IE48277B1 (en) | 1984-11-28 |
US4251539A (en) | 1981-02-17 |
DE2961653D1 (en) | 1982-02-18 |
NO791428L (en) | 1979-10-30 |
AU522924B2 (en) | 1982-07-01 |
YU102179A (en) | 1983-02-28 |
DK150602C (en) | 1987-12-07 |
CS207788B2 (en) | 1981-08-31 |
YU40994B (en) | 1986-10-31 |
JPS6320819B2 (en) | 1988-04-30 |
CA1128051A (en) | 1982-07-20 |
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